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Periodontitis-causing gene regulates key genes of glucose and fatty acid metabolism

By Dental Tribune International
August 02, 2013

KIEL, Germany: ANRIL is considered the strongest genetic risk locus of coronary artery disease and periodontitis. However, its role in causing both diseases was unclear until recently. Scientists at the Institute of Clinical Molecular Biology at the University of Kiel (CAU) and the University Medical Center Schleswig-Holstein (UKSH) have now decoded 208 major functions of the gene.

With colleagues at VU University Amsterdam and the University of Bonn, the researchers were able to demonstrate that isoforms of ANRIL regulate other genes that lie far from their sources in the human genome. In addition, the research team discovered more genetic risk variants that play a role in the manifestation of coronary artery disease and periodontitis.

To track the roles of ANRIL, CAU genetics researcher Dr Arne Schäfer and a team of scientists developed a molecular biological construct able to switch ANRIL on and off at defined time-points. This construct was then introduced into cell cultures. A small hairpin RNA, an RNA sequence that forms a hairpin structure, makes the cells destroy their own RNA specifically. Consequently, the target gene is silenced. “We tricked the cells’ immune system to see which genes are up- or down-regulated when ANRIL is switched off,” said Schäfer. The biologists observed 22,000 gene products over different periods, after having shut down ANRIL. Each time, three genes were reduced in their function: the ADIPOR1 gene, VAMP3 gene and C11ORF10 gene—all of which have an important association with glucose and fatty acid metabolism.

In the world’s largest study of periodontitis patients, the European Periodontal Genetics Consortium, the researchers found another genetic risk variant by studying the DNA of 870 periodontitis patients and a control group of 2,700 healthy people. This finding was validated in more than 21,000 heart attack patients and 44,000 controls of the largest European group of myocardial infarction patients (CARDIoGRAM). The section of DNA in which this variant is located (upstream of the VAMP3 gene within the CAMTA1 gene) is associated with a significantly increased incidence of pathogenic periodontal germs. “In the target group of periodontitis patients, we focused on normal-weight individuals under the age of 35 in order to ensure the independence of the findings from other causes of disease, such as decades of smoking and obesity. The findings of the enormous random sample of European heart attack patients, which proved to be independent of age and sex, indicate the general significance of the correlations found for this disease,” said Schäfer in explaining the results of his research.

The team from CAU and UKSH also identified new genetic risk variants of periodontitis within the C11ORF10–FADS gene cluster. They have long been associated with the development of metabolic syndrome (diabetes mellitus, impaired glucose tolerance, insulin intolerance, hypertension, abdominal obesity) and chronic inflammatory bowel disease.

“Our findings are a very big step forward for us in researching genetic causes of myocardial infarction,” said Schäfer. “They also suggest that a disturbed glucose and fatty acid metabolism, probably owing to its effects on the formation of inflammatory mediators, plays a significant role in the development of periodontitis. Periodontal disease and atherosclerosis, which often leads to heart attacks, seem to have a common causal relation, which may possibly also be found in processes of fatty acid metabolism.”

The study, titled “The large non-coding RNA ANRIL, which is associated with atherosclerosis, periodontitis and several forms of cancer, regulates ADIPOR1, VAMP3 and C11ORF10”, was supported by the Deutsche Forschungsgemeinschaft and published online on 27 June in the Human Molecular Genetics journal.

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